Both polysialosides and polysulfates are known to interact with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. However, a comprehensive site by site analysis of their binding affinities and potential synergistic antiviral effects have not been performed. Here, we report on the synthesis of polysialosides with nanomolar binding affinities to spike proteins of SARS-CoV-2 in solution using microscale thermophoresis. The dendritic polyglycerol based polysialosides dPG500SA0.55 and dPG500SA0.25, with a dissociation constant Kd of 4.78 nM and 10.85 nM, respectively, bind ~500 times stronger than the high density polysulfated analog dPG500S0.55, to intact SARS-CoV-2 virus particles or isolated spike protein. In fact, the presence of sulfate groups in a heteromultivalent compound dPG500SA0.20S0.20 weakens the binding to spike proteins. A polycarboxylated analog does not bind to SARS-CoV-2, ruling out that the interaction of polysialoside is simply driven by electrostatics. Using explicit-solvent all-atom molecular dynamics simulations and ensemble docking studies, we obtain atomistic details on the interaction of different functional groups with the SARS-CoV-2 RBD. Our data support the conclusion that sialosides interact stronger than sulfates for their binding with RBD of SARS-CoV-2. Notably, our most affine binder dPG500SA0.55 inhibits SARS-CoV-2 (WT, D614G) replication up to 98.6% at 0.5 μM concentrations.